DNA is constantly exposed to endogenous and exogenous agents that damage it producing single strand breaks, double strand breaks, interstrand cross-links and nucleotide modifications known as lesions. DNA damage has tremendous impact on human health. It is associated with aging, and the development of diseases such as cancer, and other genetically based diseases. DNA is also the target of cytotoxic therapeutic agents (e.g. -radiolysis and some antitumor antibiotics). For instance, ionizing radiation is the most common nonsurgical method used to treat cancer. Although the connection between DNA damage and cellular transformation and cytotoxicity is well established, exactly how various types of DNA damage give rise to these endpoints are not well understood. The goals of this research are to understand what the consequences of lesions produced in DNA are. Our efforts are focused on the repair and reactivity of (oxidized) abasic lesions, alkylated DNA, and an under studied lesion produced upon C5'-oxidation. We utilize organic chemistry to synthesize homogeneous nucleic acid substrates containing these molecules, which facilitates examination of their reactivity and interactions with enzymes. Using this approach we intend to look beneath the surface of DNA damage and determine what makes specific forms of DNA damage deleterious. We will examine whether the histone proteins within nucleosomes transform DNA lesions into more deleterious forms of damage and what the downstream biochemical consequences of this catalysis are. For instance, we discovered that histones catalyze DNA chemistry and are modified in the process. We will determine whether this occurs in cells and what the effects of histone modification are. We also ask whether specific forms of DNA damage inhibit repair enzymes. These investigations shed light on the (bio)chemical basis for the cytotoxicity of DNA damaging agents and provide the impetus for the design of new approaches for inducing the biochemical consequences of DNA damage. For instance, we are developing inhibitors that inactivate DNA polymerase and potentiate the effects of a cytotoxic DNA damaging agent. In summary, the project combines organic chemistry, biochemistry, and biology with the goal of understanding how DNA damage affects human health and when opportunities present themselves, to exploit this knowledge.